Hyperandrogenism

Beata Banaszewska

Department of Infertility and

Reproductive Endocrinology

Androgens are C-19 steroids produced in:

Ovary Adrenal gland

Androgens are metabolised in: Skin Adipose tissue Liver Placenta

The production rate of testosterone in the normal female is 0.2 to 0.3 mg/day

Normal total testosterone concentration in serum is below 0.8ng/ml

Testosteron is transported:

Normal women Hirsute women

80% SHBG 79% SHBG

19% Albumin 19% Albumin

1% Free 2% Free

The main androgens Dehydroepiandrosterone (DHEA)-a weak carbon-5

androgen secreted principally by the andrenal glandAndrostendione (A) - a weak carbon-4 androgen secreted

in equal amounts by the adrenal glands and ovariesTestosterone (T)- a potent carbon-4 androgen secreted by

the adrenal glands and ovaries and produced in adipose tissue from the conversion of androstendione

Dihydrotestosterone (DHT)-even more potent than testosterone.The conversion from testosterone is the result of action of 5 reductase

Origin of circulating androgens

Testosterone Androstendione DHA DHAS

25%

25%

99%90%50%

50%

50% 10%

OVARY

ADRENAL CORTEX

Causes of hyperandrogenism:PCOS 75%

Idiopatic hirsutism 15%

Adrenal hyperplasia 3%

Cushing’s disease 1%

Hyperprolactinemia 1%

Tumor of the ovary 1%

Tumor of the adrenal 0,1%

After medications 1%

Hyperandrogenism- clinical symptoms:

Irregularity of menstrual cycle Hirsutism Acne Clitorimegaly Alopecia Deepending of the voice The changes in the body shapes Increased muscular mass Infertility

Hirsutism It is cutaneus manifestation of

hyperandrogenism Women have male-pattern hair growth In areas :

– upper lip – chin– sideburn area – upper neck – chest– upper arm– lower abdomen– intergluteal region– perineum– thigh

Hirsutism rating scale by Ferriman Gallwey>8 points - hirsutism

Polycystic ovary syndrome (PCOS)

5-10% of women in reproductive ageHyperandrogenismAmenorrhoea Anovulation InfertilityObesity

The clinical consequences of chronic anovulation in PCOS women

Infertility Oligomenorrhea and amenorrhea Hirsutism and acne An increased risk of endometrial cancer An increased risk of cardiovascular disease An increased risk of diabetes mellitus in

patients with hyperinsulinemia

Sign and symptoms of PCOS patients

Observation Average incidenceInfertility 75%

Hirsutism 56%

Amenorrhea 47%

Obesity 33%

Regular menses 16%

Virilisation 17%

Endocrine abnormalities in PCOS

testosterone or normal LH/FSH ratio Normal Estrogens SHBG or normal Insulin or normal Prolactin or normal DHS

Characteristic of the polycystic ovary

The surface area is doubled The number of growing and atretic

follicles is doubled (Each ovary may contain 20-100 cystic follicles)

The thickness of the tunica is increased by 50%

There are 4 times more ovarian hilus cells nests

The Polycystic Ovary on ultrasound

The ovaries have pericentic cysts of 5 to 10 mm - usually at least 10 in one sonographic plane

Increased ovarian stromaOnly 75-80% wonem with the clinical diagnosis of PCOS had

polycystic ovaryPrevalence of the polycystic ovaries in 16 to 23% of „normal”

womenIn 50% women with hyperprolactinemia24% of women with hypothalamic amenorrhoea100% of women with CAH

Constitutional hirsutism

Women with greater activity of 5 reductasein in the skin

Normal ovulationRegular menstrual cycleNormal hormone concentrations

Polycystic ovary syndrome (PCOS) -patogenesis

Insulin resistance:-postreceptor defect in tyrosine kinase

activity , dysfunction of GLUT-4-defect of insulin receptor-anti-receptor antibodies

Compensatory hyperinsulinemiaDecrease in SHBG and IGFBP-1

productionExcessive androgen production

Insulina

Types of insulin resistanceTypes of insulin resistance

Type BType A

Type C

Autoantibodies to insulin receptorsGenetic defect

of insulin receptor(Kahn syndrome)

Defect of tyrozine kinase

tyrozine kinase

Wchich comes first, the hyperinsulinemia or the hyperandrogenism ?

There are 6 reasons that hyperinsulinemia causes hyperandrogenism The administration of insulin to women with PCOS increases circulating

androgen levels The administration of glucose to women with PCOS increases the circulating

levels of both insulin and androgen Weight loss decreases the levels of both insulin and andrgens In vitro , insulin stimulates thecal cell androgren productions The experimental reduction of insulin levels in PCOS women reduces

androgen levels After normalisation of androgen with GnRH agonist treatment, the

hyperinsulin response toglucose tolerance testing remains abnormal in obese women with polycystic ovaries

IGFBP-1

IGF1

HyperinsulinemiaHyperinsulinemia

Ovarian stymulationOvarian stymulation

HyperandrogenizmHyperandrogenizm

Insulin resistanceInsulin resistance

Genetic defects of insulin receptor

Autoantibodies to insulin receptor

Ovarian insulin receptors LH/FSH

Ovarian IGF-I receptors

PCOSPCOS Hyperthecosis

SHBG

FreeTestosterone

Defects of tyrosine kinase

cholesterol

Pregnenolone Progesterone

17hydroksyprogesterone

Androstenedione

Testosterone

THECA CELL

GnRH pulse frenuency

LH/FSH ratio

LH receptor

InsulinIGF receptor

17hydroksylase

17-lyase

17-reductase

StepsinvolvingP450c17

Ovarian defect in the pathogenesis of PCOS

Dysregulation of cytochrome P450c17 that results in :– increased activity of 17hydroksylase

– disordered 17,20-lyase activity

– excessive ovarian androgen production

There is hypothesis that hyperinsulinemia stimalates ovarian cytochrome P450c17

Defect in 3-hydroksysteroid dehydrogenase or aromatase activity

Two Clinical categories of Functional Ovarian Hyperandrogenism

Hyperandrogenism Hyperandrogenism with insulin resistance without insulin resistance

Testosterone Elevated ElevatedFasting insulin Elevated Normal or minimally

elevatedLH Minimally elevated Markedly elevated

LH response Normal Exaggerated to GnRH

DHAS Low-normal Normal or elevated

Ovarian pathology Stromal hyperthecosis Polycystic ovaries

Differentation of hyperandrogenism

Diagnosis Menstrual Total DHAS LH 17OHProg Sourse of Pattern Testoste- Androgens

rone

PCOS Irregular Elevated Elevated Elevated Normal OVARY

Hyper- Amenorrhea Elevated Normal Normal Normal OVARYthecosis often>1.5

ng/ml

Idiopatic Regular Normal Normal Normal Normal SKINhirsutism

Adrenal Irregular Elevated Often Usually Elevated ADRENALhyperpla- Normal Normal >4ng/mlsia at 8pm in

follicular phase

Congenital adrenal hyperplasia (CAH)

Enzyme deficiency: 21 hydroksylase deficiency (85% of cases of

CAH) -without sait wasting– cortisol– 17OHprog, DHAS– 17-KS, prednantiol, pregnandiol

21 hydroksylase deficiency -with sait wasting11-hydroksylase deficiency

Late onset adrenal hyperplasia sometimes occurs in women in reproductive age.

Differentation of ovarian and adrenal hyperandrgenism

DHAS

17-OH Progesterone

17-KS

Test with dexamethasone

Treatment of infertile PCOS women

Induction of ovulation – Clomiphene citrate– gonadotropins

Treatment of hyperinsulinemia– weight loss– metformin, troglitasone

Surgical treatment– ovarian wedge resection by laparotomy– ovarian wedge resection by laparoscopy– ovarian cauterisation by laparoscopy

OGTT in PCOS

Chang et al 1983, JCEM, 57:356

Hyperinsulinemia treatment

Metformin

Troglitasone

Weight loss

Metformin

Biguanide used in NIDDMInhibits hepatic glucose production Suppresses intestinal glucose absorptionIncreases insulin sensitivity in

peripheral tissuesRegulates lipid metabolism

Metformin in PCOS therapyImprovement in insulin sensitivity,

hyperinsulinemia and androgen levelsVelazquez et al. 1994, Metabolism, 43, 647-54;Velazquez et al. 1997, Metabolism, 46, 454-7; Nestler et Jakubowicz, N Engl J Med., 335, 617-23

Significant decrease in BMI and WHRVelazquez et al. 1994, Metabolism, 43, 647-54

Improvement of menstrual regularityMorin-Papunen et al..1998, Fertil Steril, 69, 691-6, Velazquez et al. 1997, Obstet Gynecol, 90, 392-9

No beneficial effects in some studiesAcbay et al,1996 Fertil Steril, 65, 949-9; Ehrmann et al., 1997, JCMB, 82, 524-30

No data on effects on clinical parameters : hirsutism and acne

Effect of metformin therapy on insulin

* statistically different, p<0,001

0

5

10

15

20

25

30

35

Insu

lin

(U

/ml)

Insulin before treatment

Insulin after treatment

*

mean +/_ SEM

0

0,2

0,4

0,6

0,8

1

1,2

1,4

Tes

tost

eron

e (n

g/m

L)

Testosterone before treatment

Testosterone after treatment

*

Effect of metformin therapy on testosterone

* statistically different, p<0,001

mean +/_ SEM

* statistically different, p<0,05

Effect of metformin therapy on SHBG

0

10

20

30

40

50

60

SH

BG

(n

mol

/L)

SHBG before treatment

SHBG after treatment

*

mean +/_ SEM

Effect of metformin therapy on FTI

* statistically different, p<0.001

mean +/_ SEM0

5

10

15

20

25

FT

I

FTI before treatment

FTI after treatment

*

Effect of metformin therapy on LH, FSH and LH/FSH ratio

0

5

10

15

LH

(m

IU/m

L)

0

5

10

15

FS

H (

mIU

/mL

)

0

5

10

15

LH

/FS

H

Before treatment

After treatment

LH FSH LH/FSH

mean +/_ SEM

Effect of metformin therapy on body mass index

* statistically different, p<0.005

mean +/_ SEM

0

10

20

30

40

BM

I (kg

/m2)

BMI before treatment

BMI after treatment

*

0

20

40

60

80

Len

ght

of m

enst

rual

cyc

le (

day

s) Lenght of cyclebefore treatmentLenght of cycle aftertreatment

Effect of metformin therapy on lenght of menstrual cycle

mean +/_ SEM

* statistically different , p<0,001

*

Effect of metformin therapy on WHR

* statistically different, p<0.001

mean +/_ SEM0

0,2

0,4

0,6

0,8

1

1,2

WH

R

WHR before treatment

WHR after treatment

*

Troglitasone Mechanism of action is not completely

anderstood Enhance insulin action without insulin

secetion It is a selective ligand for peroxisome

proliferation-activated receptor in adipose tissue

hepatotoxity ?

Results of clomiphene therapy in PCOS patients

Ovulation 80%Pregnancy rate 75%Pregnancies/ovulatory cycle 25-35%Multiple pregnancies 8%Abortion rate 30-40%

Results of gonadotropin therapy in PCOS women

Ovulation 90%Pregnancy rate 70%Pregnancies/ovulatory cycle 25-30%Multiple pregnancies 10%Abortion rate 25-30%

Women with PCOS have a higher incidence

of ovarian hyperstimulation syndrome after

ovulation stymulation

Treatment of hirsutism Cyproterone acetate (It bloks androgen

action by competitive binding to androgen receptor) 50-100mg/day on days 5-14 of the cycle nad ethinyl estradiol 30-35ug/day on cycle days 5-25 or combination of CPA (2mg/day) and EE (35ug/day) on cycle days 5-25

Spironolactone (aldosteron antagonist) 50-200mg/day between days 4 and 22 of cycle ; 50-75mg/day-mild to moderate hirsutism; 100-200mg/day severe hirsutism

Flutamide (used in prostate cancer ,It inhibits the binding of 5-DHT to androgen receptor ;250mg twice a day - it was used continuosly

Cimetidine (Imidazole is an antagonist of H2 receptor) 300mg four to five times daily for3-12 months

Androgen-producing ovarian neoplasm

Sertoli-Leydig cell tumors (Androblastoma, Arrhenoblastoma)

Hilus cell tumors Lipoid cell tumor Granulosa-theca cell tumors on ocassion Gynandoblastoma in wchich both granulosa

and leydig cell elements coexist

<1% of all ovarian tumors

Androblastoma Sertoli-Leydig cell tumors The ovarian neoplasms secrete testosterone Less than 0.4% The tumors occur in women between the

ages of 20 and 40 The most often unilateral Rapid onset of hirsutism and virilisation Surgical treatment

Gynandroblastoma Tumors have both granulosa cells and

androblastoma components Masculinisation Estrogen production produce

endometrial hyperplasia and irregular uterine bleeding

Surgical treatment

Iatrogenic androgen levels

Danazol• It is administered in endometriosis• Spome women develop hirsutism, acne

and deepening of the voice

Oral contraceptives• Progestins compartment• Ralely women develop acne and even

hirsutism

Hyperandrogenism and menopause

The high circulating LH levels activates ovarian stroma and hilus cells steroidogenesis

The menopausal ovary is a major source of testosterone, secretes moderate amounts of androstendione

The pattern of androgen secretion is changed:

Before menopause After menopause

A>>T T>A

Increased risk of diabetes mellitus in PCOS women

PCOSAge 40-49 lat 50-61 latWHR 0.81 +/- 0.06 0.84+/- 0.09Diabetes (%) 11.1 20.0

Controls

Age 40-49 lat 50-61 latWHR 0.78 +/- 0.06 0.79+/- 0.09Diabetes (%) 3.5 1.3

Dahlgren, Acta Obstet Gynecol Scand,1992,71,599

Abnormalities in lipid profile in PCOS women

Increased total cholesterolIncreased triglyceridesIncreased LDLDeacrised HDL

Talbott et al.,1998,J Clin Epidemiol,51,41Conway et al.,1992,Clin Endocrinol,37,119von Eckardstein,1996,Gynecol Endocrinol,10,311

Abnormalities in lipid profile in PCOS women

Abnormal lipids pattern is independent

of body weight

Wild et al.,1992, Am J Obstet Gynecol,166,1191Graf et al., 1990, Clin Endocrinol,33.119

Insulin resistance and Hyperinsulinemia

Advers lipid profile

Glucose intoleranceNIDDM

Cardiovascular disease

PAI-1

Obesity